The current invention relates to the field of medical treatment which is characterized by the absence or diminution of control of sphincters of the gastrointestinal and urinary tracts, especially, that lack of control as seen in patients with hormonal deprivation or imbalance, e.g., post-menopausal women.
Sphincters are structures in the body which regulate the flow of materials between the interior and exterior of the body or between various structures within the body. They function in much the same manner as a gate or valve in a pipe. Sphincters are composed of rings or flaps of either striated or smooth muscle cells between different luminal structures: interior, e.g., between the lower esophagus and upper part of the stomach or between the bladder and the posterior urethra; exterior, e.g., the lower colon and the exterior (the anal sphincter). Sphincters composed of striated muscle and controlled by the sympathetic nervous system can, to some extent, be directed by conscious action, e.g., the external urethral sphincter or the upper esophageal sphincter. Sphincters composed of smooth muscle cells are mainly controlled by the parasympathetic nervous system and are not consciously controlled. Smooth muscle sphincters are controlled by internal signals relating to the conditions in the luminal areas on either side of the sphincter, e.g., food traveling down the esophagus triggers the lower esophageal sphincter to relax or open to the stomach, or pressure in the bladder signals the sphincter to the posterior urethra to open. Opening of a sphincter is accomplished by the relaxation of the muscle's tone. Normally, most sphincters maintain remain closed or contracted in relation to their attached luminal structures, thus shutting off the flow of materials. Failure of sphincters to operate properly may be due to a variety of causes such as an obstruction in the passage, mechanical disruption of the passage by trauma or surgery, improper regulation by signals of the nervous system, or loss of muscle tone due to deterioration of the muscle, often seen in aging or with the loss of homeostatic balance of hormones. (For further details see: "Harrison's Principles of Internal Medicine", 9th Ed., Isselbacher, et al., McGraw-Hill Book Co., NYC, Chap.44, p. 22-3 and Chap. 239, p. 1365-7.)
It is the failure of sphincters due to the loss of hormonal balance and their sequelae which are most germane to the current invention. In particular, the sphincter failure and resulting conditions germane to this invention would be: failure of the posterior urethral sphincter leading to urinary incontinence, failure of the anal sphincter leading to fecal incontinence, and failure of the lower esophageal sphincter leading to gastroesophageal reflux disease.
Urinary incontinence is a common problem with the elderly population with at least 15% incidence. The incidence increases to 60% in patients living in community care facilities (nursing homes). Although the condition is not life-threatening, it is a source of both embarrassment to the patient and a potential problem for the maintenance of proper hygienic care for this population. In economic terms, urinary incontinence represents a substantial cost for the institution providing care for the aged. There are two major types of urinary incontinence which are common to the aged. The first type is stress incontinence which the is inability to hold back micturition when a physical stress is placed in the intraabdominal area, e.g., laughing, coughing, or stressful physical activity. The second type is urge incontinence where the patient can not delay voiding when the bladder is perceived to be full. Both of these types are common in post-menopausal women, especially parous women with weaken or damaged pelvic muscles and ligatures due to child birth. Treatment of this condition may be palliative such as using absorbent undergarments or in severe cases the use of alpha adrenergic blockers such as clonidine. However, agents such as clonidine have substantial cardiovascular side-effects which can make them not useful for chronic administration for urinary incontinence as a sole indication. Much more successful for the chronic treatment urinary incontinence in post-menopausal women is the use of estrogen hormone replacement therapy (HRT).
HRT is not usually indicated for the singular use for treatment of urinary incontinence; however, this is a beneficial effect. However, HRT is plagued with poor patient compliance due to the negative side-effects, e.g., increased risk of uterine cancer with un-opposed estrogen, negative CNS effects when estrogen is combined with progestins, bloating, re-initiation of menses, increased breast cancer risk, etc. Certainly, estrogens are not usually used in males. Therefore, there is a need for better therapies to urinary incontinence, especially in the elderly.
Fecal incontinence occurs in the elderly population in a pattern similar to that seen with urinary incontinence; however, at a much reduced rate. The consequence of patients suffering from this condition can be much worse than those suffering from urinary incontinence in that hygiene becomes a much more serious problem. More care and economic outlay must be used to avoid such problems as infection with this population. Causes for fecal incontinence appear to be similar to those which cause urinary incontinence and therefore, the patient population suffering from this malady is similar, i.e., parous post-menopausal women are the most common suffers. Treatment for this condition is confined to palliative measures, such as absorbent undergarments, frequent changes of garments, and frequent bathing. The use of HRT in post-menopausal women as an effective treatment is not clear, although there is every reason to believe that it has the potential for beneficial effects. Perhaps, the lack of clarity is due to the idiosyncratic nature of this condition or the fact that insufficient data exists because of the relatively few women who will tolerate the negative side-effects of HRT, especially older(70+) post-menopausal women who are the most likely to suffer. It is clear that better therapy in this area would be of benefit. (Further details see; "Hormones and Aging", Ed. Timiras et al., CRC Press, Boca Raton Fla., Chap. 8, p.141-142 and references therein.)
GERD is a condition where the contents of the stomach are spilled up (refluxed) into the esophagus. This condition is often due to a failure of the lower esophageal sphincter to close properly. The consequences of this reflux are annoying to the patient and potentially serious. In milder forms, the patient complains of a burning sensation in the esophagus or heartburn and this often leads to pain, lack of sleep, and loss of productivity. In more serious cases, chronic reflux can lead to ulceration of the esophagus leading to surgical intervention or it is thought to be contributory to the development of esophageal cancer.
People of all ages and sexes can suffer from this malady; However, it is more prevalent in the older population. Anecdotally, women report changes (increase or decrease in symptoms) during menstrual cycles, during pregnancy, and during menopause, yet verification of a linkage between hormonal levels and GERD remains illusive. It is well known that hormones such as estrogen effect other sphincters of similar physiology and it is known that estrogens effect stomach motility and other upper GI functions such as gastric emptying. However, other factors causing failure of the esophageal sphincter, such as herniation of the stomach, hypersensitivity of the esophagus and hyperacidity of the stomach, may cloud a clear understanding of the role of hormones in this condition.
Treatment for GERD consists of mechanical and pharmacologic intervention. Mechanical intervention can be achieved by in several ways, patients who suffer GERD at night can sleep in a more elevated position, thus allowing gravity to keep the stomach's contents from entering the esophagus, obese patients can lose weight, exercise can increase the tone of the supporting muscles, or surgical intervention can be used to repair the effected tissues. Pharmacological intervention consists of lowering the stomach's acidity with antacids or with anticholinergic drugs, such as bethanechol, each or both of these may be effective, but are problematic for long term use due to negative side-effects. New agents by themselves or in addition to known, effective agents would improve current therapies for the treatment of GERD.
The present invention is directed to the discovery that the compounds of the present invention, as defined below, increase sphincter competence.